A major theory of aging is that oxidative damage and mitochondrial dysfunction may play a role and this may contribute to the age-dependent incidence of neurodegenerative diseases such as Alzheimer's disease (AD). Mitochondrial dysfunction could play either a primary role or a secondary role as a risk factor in the pathogenesis of AD. Recent studies of peripheral tissues show age-dependent impairment of mitochondrial function however little information is available concerning the effects of aging on either mitochondrial function or oxidative damage to DNA or proteins in human brain. Our fist specific aim will be to determine whether there are age-dependent changes in the activities of the 4 mitochondrial electron transport chain complexes and ATP synthase in human brain tissue of neuropathologically normal individuals aged 30 to 100. We will determine the regional distribution of any changes and whether they correlate with markers of oxidative damage to DNA and protein. Measurements of 8-hydroxy-2-deoxyguanosine will be made as a marker for oxidative damage to nuclear and mitochondrial DNA, while measurements of protein carbonyl groups will be an indicator of oxidative damage to proteins. Or second specific aim is to determine whether there is an abnormality in any of the electron transport chain complexes and ATP synthase in AD postmortem brain tissue as compared with age-matched controls. We will determine whether changes are confined to one enzyme complex, and the regional distribution of changes. We will also determine whether markers of oxidative damage to DNA and protein are increased in AD mutations in mitochondrial DNA which have been associated with AD pathology. We will be able to compare neurochemical changes in these brains with those which occur in sporadic AD brains. In order to determine whether energy deficits are localized to brain or exist systemically, we will also look for evidence of mitochondrial dysfunction and oxidative damage to DNA in lymphoblastoid cell lines from familial AD patients a compared with normal controls. Finally, we will develop experimental animal models to determine whether either local or systemic administration of mitochondrial toxins can reproduce the pattern of cellular damage, and some of the characteristic histopathologic and neurochemical features of AD. We will focus on changes in the entorhinal cortex and hippocampus. We are particularly interested in developing a model involving chronic systemic administration of a mitochondrial toxin, and to determine the effects of aging on the lesions. We will also investigate potential therapeutic strategies in these models. These studies will help to elucidate the role of mitochondrial dysfunction and oxidative damage to DNA and protein in both normal aging and in the pathogenesis of AD.